Cardiovascular abnormalities in chest radiographs of children with pneumonia, Uganda

Abstract Objective To describe chest radiograph findings among children hospitalized with clinically diagnosed severe pneumonia and hypoxaemia at three tertiary facilities in Uganda. Methods The study involved clinical and radiograph data on a random sample of 375 children aged 28 days to 12 years enrolled in the Children’s Oxygen Administration Strategies Trial in 2017. Children were hospitalized with a history of respiratory illness and respiratory distress complicated by hypoxaemia, defined as a peripheral oxygen saturation (SpO2) < 92%. Radiologists blinded to clinical findings interpreted chest radiographs using standardized World Health Organization method for paediatric chest radiograph reporting. We report clinical and chest radiograph findings using descriptive statistics. Findings Overall, 45.9% (172/375) of children had radiological pneumonia, 36.3% (136/375) had a normal chest radiograph and 32.8% (123/375) had other radiograph abnormalities, with or without pneumonia. In addition, 28.3% (106/375) had a cardiovascular abnormality, including 14.9% (56/375) with both pneumonia and another abnormality. There was no significant difference in the prevalence of radiological pneumonia or of cardiovascular abnormalities or in 28-day mortality between children with severe hypoxaemia (SpO2: < 80%) and those with mild hypoxaemia (SpO2: 80 to < 92%). Conclusion Cardiovascular abnormalities were relatively common among children hospitalized with severe pneumonia in Uganda. The standard clinical criteria used to identify pneumonia among children in resource-poor settings were sensitive but lacked specificity. Chest radiographs should be performed routinely for all children with clinical signs of severe pneumonia because it provides useful information on both cardiovascular and respiratory systems.


Introduction
Pneumonia is a leading cause of morbidity and mortality in children globally, accounting for around one million fatalities each year, with the largest burden in low-and middle-income countries. 1,2 World Health Organization (WHO) guidelines describe clinical signs and symptoms for diagnosing pneumonia in children. 3,4 These guidelines are widely used in Africa, including Uganda. One limitation is that the clinical criteria are broad and are intended to maximize their sensitivity for detecting severe pneumonia at the expense of specificity. 5 This approach can result in the overdiagnosis of severe pneumonia, thus delaying the definitive diagnosis of other conditions with a similar presentation, potentially leading to mismanagement and increasing the risk of morbidity or mortality. 6 Although pulse oximetry is helpful for identifying patients with hypoxaemia who require supportive oxygen therapy, its use does not increase the specificity of the guidelines' diagnostic criteria. 6 In addition, WHO recommends chest radiography examinations for children with severe pneumonia to confirm the diagnosis and exclude complications. A chest radiograph reporting tool for diagnosing pneumonia in children has been developed to enable researchers to standardize the ra-diological interpretation of abnormal lung findings. 4,7,8 This WHO-recommended tool classifies significant pathology as the presence of lung consolidation, lung infiltrates or pleural effusion and gives definitions for these entities. 9 The tool has been evaluated previously and found to be reliable, with good intra-and inter-observer agreement. [8][9][10] Other radiological parameters can also be assessed on chest radiographs, such as the cardiothoracic ratio, which can be used to diagnose cardiomegaly. Findings may also indicate the presence of heart failure, congenital lung or heart abnormalities, or pulmonary oedema, all of which can have a similar clinical presentation to severe pneumonia.
Previously, in the Children's Oxygen Administration Strategies Trial (COAST) in African children with severe pneumonia, 11 we used the WHO-recommended tool for interpreting chest radiographs to define radiological pneumonia.
The objective of the current study, which was nested within the trial, was to describe chest radiograph findings among Ugandan children hospitalized with a clinical diagnosis of severe pneumonia and hypoxaemia. Better understanding of chest radiograph findings in children who present to hospital with clinical signs of pneumonia can help guide public health measures targeting pneumonia.

Methods
We performed a cross-sectional study of chest radiograph findings among Ugandan children hospitalized with severe pneumonia and hypoxaemia who were taking part in COAST (IS-RCTN15622505; registered: 20 February 2016), which was a multisite, randomized, controlled trial designed to identify the best oxygen delivery strategies for reducing in-hospital morbidity and mortality in African children with respiratory distress complicated by hypoxaemia. The study involved three tertiary health-care facilities in Uganda: (i) Mulago Hospital, which is the national referral hospital for the entire country and a primary healthcare facility for the metropolitan area of Kampala, Uganda's capital; 12 (ii) the Mbale regional referral hospital, which is a semi-rural government hospital situated 250 km north-east of Kampala; and (iii) the Soroti regional referral hospital, which is a rural government hospital situated 320 km north-east of Kampala. Mulago Hospital has 1790 beds and around 20 000 paediatric admissions annually; Mbale hospital has 470 beds and around 17 000 paediatric admissions annually; and Soroti hospital has 250 beds and around 8000 paediatric admissions annually. 13 Children included in the trial were aged between 28 days and 12 years, had a history of respiratory illness and had been hospitalized with respiratory distress complicated by hypoxaemia, which was defined as a peripheral oxygen saturation (SpO 2 ) under 92%. 14 Excluded from the trial were children with chronic lung disease or cyanotic heart disease and those who had received more than 3 hours of oxygen therapy at another centre before referral. 11 All children were reviewed by a study clinician, and pneumonia was managed in accordance with WHO guidelines. 4 For this analysis, we used proportionate random sampling to select 384 children who had been enrolled at the three trial sites in 2017 (Fig. 1). The sample size was calculated using the Kish-Leslie formula and was based on the prevalence of radiological pneumonia (as defined by WHO) reported in the Pneumonia Etiology Research for Child Health (PERCH) project, which was performed in a setting similar to ours. 15,16 Chest radiographs of the participants selected were retrieved, de-identified and a quality assessment was conducted by one study author. We excluded participants whose radiographs were uninterpretable, such that the presence or absence of radiological pneumonia could not be determined without additional imaging. The final analysis included 375 participants.
A structured, clinical case report form was completed for each child at admission and on reviews at 1, 2, 4, 8, 16, 24, 36 and 48 hours. 11 Bedside measurements included the respiratory rate, oxygen saturation, anthropometric measurements and chest auscultation; and laboratory investigations included a complete blood count, glucose and lactate point-of-care tests, and blood culture. 14 Although chest radiograph examinations were ordered at trial admission, they could not be performed immediately in most cases because mobile radiograph facilities were not available. However, as most chest radiographs were conducted before hospital discharge and as the average time to discharge was 4.8 days, 11 any delay was unlikely to have influenced the appearance of the radiograph because chest radiograph abnormalities have been reported to resolve in around seven days typically. 17 Anteroposterior views of the chest were obtained at a standard film-focus distance of 100 cm. In addition, posteroanterior views were obtained for older children who were able to stand and obey instructions. All radiographic images were digitized following a standard operating procedure in which a hand-held 20-megapixel camera (Tecno Camon X, Tecno Mobile, Shenzhen, China) was used to take pictures of radiographs mounted on a white-light viewing box. Two radiologists (author EN with either author FA or GE) reviewed the photographic images and reported cases of pneumonia using standardized WHO method for paediatric chest radiograph reporting. If there was a disagreement, a third reader blinded to the initial reports adjudicated. In addition, all radiologists were blinded to the patient's clinical diagnosis and outcomes and to the trial's randomization strategy. Radiological pneumonia was diagnosed if the chest radiograph showed evidence of consolidation, infiltrates or pleural effusion. Radiologists also reported clinical findings other than pneumonia. We used a cardiothoracic ratio cut-off of 0.6 to define cardiomegaly. Radiographs  showing characteristic chest findings are available in the online repository. 18 We recorded radiological data, including both pneumonia and nonpneumonia findings, in a database specifically developed for the study using Microsoft Access (Microsoft Corporation, Redmond, United States of America) and later exported to Stata version 13 (StataCorp LLC, College Station, USA) for analysis. Clinical data were obtained from the trial's Open Clinica database (Open Clinica, Waltham, USA) and also exported to Stata version 13.

Statistical analysis
We report patients' characteristics using means and standard deviations for normally distributed variables, and medians and interquartile ranges (IQRs) for skewed variables. Normality was ascertained using the Shapiro-Wilk test and probability plots. We report categorical variables using frequencies and proportions. Patients were divided into two groups according to their peripheral oxygen saturation: (i) those with severe hypoxaemia (i.e. an SpO 2 under 80%); and (ii) those with mild hypoxaemia (i.e. an SpO 2 of 80% or above but under 92%). We used frequencies and proportions to describe clinical findings on chest radiographs and to determine their prevalence. The prevalence of radiological pneumonia among study participants was the proportion of all radiographs reviewed that showed evidence of pneumonia, and the prevalence of other chest radiograph findings (e.g. cardiovascular abnormalities) was the proportion of all radiographs reviewed that showed evidence of those findings. The clinical characteristics of participants with severe hypoxaemia and those with mild hypoxaemia were compared using the χ 2 test for categorical variables with a cell count of five or over, and using Fischer's exact test for a cell count under five. Medians were compared using quantile regression. We used a test of proportions, with a 95% confidence interval (95% CI), to test the hypothesis that there was no difference in the proportion of children with specific chest radiograph findings between those with severe and mild hypoxaemia.
Ethical approval for the trial and for this substudy was obtained from the Institutional Research and Ethics Committee of the School of Medicine, Makerere University, Kampala (Ethics reference numbers: 2016-030 and 2019-024, respectively) and from the Research Ethics Committee at Imperial College, London (15IC3100), which was the trial sponsor. Although consent to publish individual data was not obtained from patients or their legal guardians, all data were anonymized before publication.

Radiological pneumonia
Details of the chest radiograph findings are presented in Table 2 and Fig. 1
cephalization, and 38.7% (41/106) had other cardiovascular findings such as vascular pruning, dextrocardia, scimitar syndrome, left atrial enlargement or simply an abnormal heart shape. Patients were classified on the basis of their key finding, though many had multiple abnormalities.
There was no significant difference between children with mild hypoxaemia and those with severe hypoxaemia in the proportion with cardiovascular abnormalities: the difference was 4.9 percentage points (95% CI: −6.1 to 15.9). Nor did we find a significant difference in the proportion with cardiovascular abnormalities between children who were younger than 1 year, or 1 year or older (difference: 6.9 percentage points; 95% CI: −8.1 to 22.1) or between males and females (difference: 4.2 percentage points; 95% CI: −4.9 to 13.4). Furthermore, there was no significant difference between children with and without car- a We defined mild hypoxaemia as a peripheral oxygen saturation of 80% or above but below 92% and severe hypoxaemia as an SpO 2 < 80%. b We defined tachypnoea as a respiratory rate ≥ 60 breaths/min for children aged under 2 months, ≥ 50 breaths/min for those aged over 2 months and under 1 year, ≥ 40 breaths/min for those aged 1 year or more and under 6 years, and ≥ 30 breaths/min for those aged ≥ 6 years. c Data were either missing, invalid or not recorded for some children. d We defined compensated shock as one or more signs of impaired perfusion: (i) capillary refill time ≥ 2 s; (ii) a temperature gradient on limbs; (iii) a weak radial pulse; or (iv) severe tachycardia. e Altered consciousness was determined according to voice and pain responses on the AVPU scale. f We defined severe anaemia as a haemoglobin concentration < 5 g/dL. g We defined leucocytosis as a white blood cell count > 11 × 10 3 cells/µL. h We defined hypoglycaemia as a blood sugar concentration < 3 mmol/L. I We defined hyperlactataemia as a blood lactate concentration > 5 mmol/L.

Discussion
We evaluated chest radiograph findings in 375 children aged 28 days to 12 years who were diagnosed with severe pneumonia, the majority (60%) younger than 1 year. We found that almost half had radiological pneumonia, while more than a third had normal chest radiographs. A third of children had other findings, of which more than four fifths had cardiovascular abnormalities. Overall, 56 children had pneumonia with other abnormalities. The prevalence of radiological pneumonia in these patients was comparable to that in similar studies. For example, a Mozambican study involving children aged 0 to 23 months who were diagnosed with severe pneumonia on the basis of clinical observations and chest radiographs interpreted using the same WHO standardized radiograph reporting format we employed, found the prevalence of radiological pneumonia to be 43%. 19 Interestingly, the Mozambican study was conducted before vaccination with the decavalent pneumococcal conjugate vaccine (PCV10) was introduced, whereas our study was conducted when national coverage was 64% for the trivalent pneumococcal conjugate vaccine and 79% for the combined vaccine against diphtheria, tetanus, pertussis, hepatitis B, polio and Haemophilus influenzae type b (DTaP-HepB-IPV-Hib). 20 As the vaccination status of trial participants was not recorded, we could not link this data to radiography findings. A second study, the multinational PERCH project, found a prevalence of radiological pneumonia of 54% (range across sites: 35 to 64%) among children aged 1 to 59 months hospitalized with WHO-defined severe or very severe pneumonia (but not necessarily with hypoxaemia) in countries where vaccination with PCV10 and H. influenzae type b vaccine had largely been introduced. 15 Neither of these two studies reported cardiovascular or cardiac anomalies.
Our study considered hypoxaemia in addition to severe pneumonia, but found no significant difference in the proportion of children with radiological pneumonia between those with severe or mild hypoxaemia. Our finding that more than one third of children had normal chest radiographs was similar to that of an Ethiopian study of 122 children aged 3 months to 14 years who were hospitalized with a diagnosis of severe pneumonia, which reported 51.6% with no radiological evidence of pneumonia. 21 In the COAST study, we reported a low level of bacteraemia, 11 which suggests that many of our patients may have had viral pneumonia with no specific changes on chest radiograph. 22 In agreement with other authors, [23][24][25] we found no correlation between radiological pneumonia and the presence of crepitations on chest auscultation.
Two advantages of our study were that radiographs were interpreted by trained radiologists and that their reports were comprehensive and included cardiovascular abnormalities. The most common cardiovascular abnormality Cardiovascular abnormalities in paediatric pneumonia, Uganda Eva Nabawanuka et al.
was cardiomegaly. Although there is a dearth of data on the prevalence of cardiovascular abnormalities in Ugandan children, researchers estimated that around 8300 Ugandan children are born annually with congenital heart disease, which corresponds to a rate of 36.6 per thousand live births annually. 26 Although chest radiograph is not the gold standard for diagnosing cardiovascular disease, it provides preliminary diagnostic information that can identify individuals for referral to echocardiography and other specific tests. [27][28][29] In 2001, researchers evaluated chest radiograph and echocardiography data from 95 children aged between 2 days and 19 years who attended an outpatient clinic and found that the cardiothoracic ratio was an acceptable predictor of cardiac enlargement. 30 A cardiothoracic ratio of 0.6 had a specificity of 93.4% for identifying cardiomegaly against the gold standard of echocardiography. The 44 children found to have a cardiothoracic ratio of 0.6 or greater in our study had not previously been diagnosed with a cardiac condition (in fact, it was an exclusion criterion) even though the prevalence of paediatric cardiac disease is relatively high in the study setting. 26 If a chest radiograph had not been performed to confirm the clinical diagnosis of pneumonia in these children, diagnosis and treatment of the heart condition could have been delayed.
The relatively high proportion of abnormal cardiovascular findings among children with severe pneumonia in our study may have occurred because cardiovascular disease is a risk factor for pneumonia. 31 However, another pos-sible explanation is that children with a cardiovascular illness may present with acute breathing difficulties, cyanosis, lethargy or another danger sign specified by the guidelines for diagnosing severe pneumonia. 4 Our study confirms that the specificity of the clinical criteria used to diagnose pneumonia in children, especially in lowresource settings, is poor. 5,32 In Africa, the specificity of these criteria is further weakened in areas where malaria is endemic because the clinical complications of severe malaria include respiratory distress (i.e. Kussmaul breathing). 33,34 However, relatively few children in our study had a diagnosis of malaria.
One limitation of our study was the lack of blood gas analysis (to provide evidence of hypercarbia) and of other investigations (e.g. echocardiography and molecular bacterial and viral analysis) that could be used to correlate clinical and radiological findings. Another limitation is that the statistical accuracy of chest radiography for identifying pneumonia is highly variable. 35 We tried to minimize inaccuracies by ensuring that radiological pneumonia was identified on radiographs independently by more than one trained radiologist using a standardized WHO tool. Although we failed to find a significant association between hypoxaemia severity and any clinical finding, the 95% CIs were wide, which suggests that a larger sample may be needed to estimate differences with good precision. Nevertheless, we were able to report other abnormal findings, such as cardiovascular conditions, which could be important for children with putative pneumonia.

Research
Cardiovascular abnormalities in paediatric pneumonia, Uganda Eva Nabawanuka et al.